Impaired overload-induced hypertrophy in obese Zucker rat slow-twitch skeletal muscle

The effect of insulin resistance (IR) on the adaptation of skeletal muscle loading is not well understood. Here we examine whether the soleus muscles of the lean Zucker (LZ) and insulin-resistant obese Zucker (OZ) rat exhibit differences in their ability to undergo muscle hypertrophy following 8 wk of mechanical overload. Four-week-old male LZ ( n = 5) and OZ ( n = 5) rats underwent unilateral surgical ablation of the gastrocnemius muscle while the contralateral hindlimb was used as an internal control. Mechanical overload increased soleus muscle wet weight (LZ 57% and OZ 33%, respectively; P < 0 .05) and average type 1 fiber cross-sectional area (LZ 32% and OZ 5%, respectively; P < 0.05) in LZ and OZ rats, while the magnitude of these increases was greater in the LZ animals ( P < 0 .05). The reduced degree of muscle hypertrophy observed in the OZ animals was associated with decreases in the ability of the OZ soleus muscle to phosphorylate p70s6kThr 389 and mTOR, while phosphorylation of p70s6kThr 389 was increased in the LZ overloaded soleus by 83% ( P < 0 .05). The amount of Tuberin/TSC2 phosphorylation, an inhibitor of mTOR, was unchanged in the LZ soleus after overload while it was increased (68.3%, P < 0.05) in OZ animals. Conversely, AMPK phosphorylation was decreased in the LZ (−22.77%, P < 0 .05) but increased (57%, P < 0 .05) in the OZ soleus with overload. Taken together, these data suggest that IR or other related comorbidities may impair the ability of the soleus to activate mTOR signaling and undergo load-induced muscle hypertrophy.

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ANG II is required for optimal overload-induced skeletal muscle hypertrophy

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2001.280.1.e150 ◽

2001 ◽

Vol 280 (1) ◽

pp. E150-E159 ◽

Cited By ~ 80

Author(s):

Scott E. Gordon ◽

Bradley S. Davis ◽

Christian J. Carlson ◽

Frank W. Booth

Keyword(s):

Skeletal Muscle ◽

Soleus Muscle ◽

Muscle Hypertrophy ◽

Ace Inhibitor ◽

Muscle Protein ◽

Ang Ii ◽

Sprague Dawley ◽

Surgical Ablation ◽

Hypertrophic Response ◽

Skeletal Muscle Hypertrophy

ANG II mediates the hypertrophic response of overloaded cardiac muscle, likely via the ANG II type 1 (AT1) receptor. To examine the potential role of ANG II in overload-induced skeletal muscle hypertrophy, plantaris and/or soleus muscle overload was produced in female Sprague-Dawley rats (225–250 g) by the bilateral surgical ablation of either the synergistic gastrocnemius muscle ( experiment 1) or both the gastrocnemius and plantaris muscles ( experiment 2). In experiment 1 ( n = 10/ group), inhibiting endogenous ANG II production by oral administration of an angiotensin-converting enzyme (ACE) inhibitor during a 28-day overloading protocol attenuated plantaris and soleus muscle hypertrophy by 57 and 96%, respectively (as measured by total muscle protein content). ACE inhibition had no effect on nonoverloaded (sham-operated) muscles. With the use of new animals ( experiment 2; n = 8/group), locally perfusing overloaded soleus muscles with exogenous ANG II (via osmotic pump) rescued the lost hypertrophic response in ACE-inhibited animals by 71%. Furthermore, orally administering an AT1 receptor antagonist instead of an ACE inhibitor produced a 48% attenuation of overload-induced hypertrophy that could not be rescued by ANG II perfusion. Thus ANG II may be necessary for optimal overload-induced skeletal muscle hypertrophy, acting at least in part via an AT1receptor-dependent pathway.

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The α7β1-integrin accelerates fiber hypertrophy and myogenesis following a single bout of eccentric exercise

AJP Cell Physiology ◽

10.1152/ajpcell.00515.2010 ◽

2011 ◽

Vol 301 (4) ◽

pp. C938-C946 ◽

Cited By ~ 29

Author(s):

Tara N. Lueders ◽

Kai Zou ◽

Heather D. Huntsman ◽

Benjamin Meador ◽

Ziad Mahmassani ◽

...

Keyword(s):

Skeletal Muscle ◽

Eccentric Exercise ◽

Time Course ◽

Muscle Hypertrophy ◽

Isometric Force ◽

Transmembrane Protein ◽

Mechanical Strain ◽

Cellular Growth ◽

Cross Sectional ◽

Single Bout

The α7β1-integrin is a heterodimeric transmembrane protein that adheres to laminin in the extracellular matrix, representing a critical link that maintains structure in skeletal muscle. In addition to preventing exercise-induced skeletal muscle injury, the α7-integrin has been proposed to act as an intrinsic mechanosensor, initiating cellular growth in response to mechanical strain. The purpose of this study was to determine the extent to which the α7-integrin regulates muscle hypertrophy following eccentric exercise. Wild-type (WT) and α7-integrin transgenic (α7Tg) mice completed a single bout of downhill running exercise (−20°, 17 m/min, 60 min), and gastrocnemius-soleus complexes were collected 1, 2, 4, and 7 days (D) postexercise (PE). Maximal isometric force was maintained and macrophage accumulation was suppressed in α7Tg muscle 1D PE. Mean fiber cross-sectional area was unaltered in WT mice but increased 40% in α7Tg mice 7D PE. In addition, a rapid and striking fivefold increase in embryonic myosin heavy chain-positive fibers appeared in α7Tg mice 2D PE. Although Pax7-positive satellite cells were increased in α7Tg muscle 1D PE, the number of nuclei per myofiber was not altered 7D PE. Phosphorylation of mammalian target of rapamycin (mTOR) was significantly elevated in α7Tg 1D PE. This study provides the first demonstration that the presence of the α7β1-integrin in skeletal muscle increases fiber hypertrophy and new fiber synthesis in the early time course following a single bout of eccentric exercise. Further studies are necessary to elucidate the precise mechanism by which the α7-integrin can enhance muscle hypertrophy following exercise.

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Effects of combined treatment with blood flow restriction and low-current electrical stimulation on muscle hypertrophy in rats

Journal of Applied Physiology ◽

10.1152/japplphysiol.00070.2019 ◽

2019 ◽

Vol 127 (5) ◽

pp. 1288-1296

Author(s):

Madoka Yoshikawa ◽

Takeshi Morifuji ◽

Tomohiro Matsumoto ◽

Noriaki Maeshige ◽

Minoru Tanaka ◽

...

Keyword(s):

Skeletal Muscle ◽

Blood Flow ◽

Electrical Stimulation ◽

Muscle Hypertrophy ◽

Combined Treatment ◽

Blood Flow Restriction ◽

Sectional Area ◽

Cross Sectional ◽

Flow Restriction ◽

Skeletal Muscle Hypertrophy

This study aimed to clarify the effects of a combined treatment comprising blood flow restriction and low-current electrical stimulation on skeletal muscle hypertrophy in rats. Male Wistar rats were divided into control (Cont), blood flow restriction (Bfr), electrical stimulation (Es), or Bfr with Es (Bfr + Es) groups. Pressure cuffs (80 mmHg) were placed around the thighs of Bfr and Bfr + Es rats. Low-current Es was applied to calf muscles in the Es and Bfr + Es rats. In experiment 1, a 1-day treatment regimen (5-min stimulation, followed by 5-min rest) was delivered four times to study the acute effects. In experiment 2, the same treatment regimen was delivered three times/wk for 8 wk. Body weight, muscle mass, changes in maximal isometric contraction, fiber cross-sectional area of the soleus muscle, expression of phosphorylated and total-ERK1/2, phosphorylated-rpS6 Ser235/236, phosphorylated and total Akt, and phosphorylated-rpS6 Ser240/244 were measured. Bfr and Es treatment alone failed to induce muscle hypertrophy and increase the expression of phosphorylated rpS6 Ser240/244. Combined Bfr + Es upregulated muscle mass, increased the fiber cross-sectional area, and increased phosphorylated rpS6 Ser240/244 expression and phosphorylated rpS6 Ser235/236 expression compared with controls. Combined treatment with Bfr and low-current Es can induce muscle hypertrophy via activation of two protein synthesis signaling pathways. This treatment should be introduced for older patients with sarcopenia and others with muscle weakness. NEW & NOTEWORTHY We investigated the acute and chronic effect of low-current electrical stimulation with blood flow restriction on skeletal muscle hypertrophy and the mechanisms controlling the hypertrophic response. Low-current electrical stimulation could not induce skeletal muscle hypertrophy, but a combination treatment did. Blood lactate and growth hormone levels were increased in the early response. Moreover, activation of ERK1/2 and mTOR pathways were observed in both the acute and chronic response, which contribute to muscle hypertrophy.

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Structural and functional remodeling of skeletal muscle microvasculature is induced by simulated microgravity

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2000.278.6.h1866 ◽

2000 ◽

Vol 278 (6) ◽

pp. H1866-H1873 ◽

Cited By ~ 108

Author(s):

Michael D. Delp ◽

Patrick N. Colleran ◽

M. Keith Wilkerson ◽

Matthew R. McCurdy ◽

Judy Muller-Delp

Keyword(s):

Skeletal Muscle ◽

Soleus Muscle ◽

Skeletal Muscles ◽

Gastrocnemius Muscle ◽

Fluid Pressure ◽

Hindlimb Unloading ◽

Cross Sectional ◽

Luminal Diameter ◽

Structural Remodeling

Hindlimb unloading of rats results in a diminished ability of skeletal muscle arterioles to constrict in vitro and elevate vascular resistance in vivo. The purpose of the present study was to determine whether alterations in the mechanical environment (i.e., reduced fluid pressure and blood flow) of the vasculature in hindlimb skeletal muscles from 2-wk hindlimb-unloaded (HU) rats induces a structural remodeling of arterial microvessels that may account for these observations. Transverse cross sections were used to determine media cross-sectional area (CSA), wall thickness, outer perimeter, number of media nuclei, and vessel luminal diameter of feed arteries and first-order (1A) arterioles from soleus and the superficial portion of gastrocnemius muscles. Endothelium-dependent dilation (ACh) was also determined. Media CSA of resistance arteries was diminished by hindlimb unloading as a result of decreased media thickness (gastrocnemius muscle) or reduced vessel diameter (soleus muscle). ACh-induced dilation was diminished by 2 wk of hindlimb unloading in soleus 1A arterioles, but not in gastrocnemius 1A arterioles. These results indicate that structural remodeling and functional adaptations of the arterial microvasculature occur in skeletal muscles of the HU rat; the data suggest that these alterations may be induced by reductions in transmural pressure (gastrocnemius muscle) and wall shear stress (soleus muscle).

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β-Cryptoxanthin Improves p62 Accumulation and Muscle Atrophy in the Soleus Muscle of Senescence-Accelerated Mouse-Prone 1 Mice

Nutrients ◽

10.3390/nu12082180 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2180

Author(s):

Mari Noguchi ◽

Tomoya Kitakaze ◽

Yasuyuki Kobayashi ◽

Katsuyuki Mukai ◽

Naoki Harada ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Mass ◽

Muscle Atrophy ◽

Soleus Muscle ◽

Muscle Fibers ◽

Skeletal Muscle Atrophy ◽

Related Factor ◽

Related Factors ◽

Cross Sectional ◽

Senescence Accelerated Mouse

We investigated the effects of β-cryptoxanthin on skeletal muscle atrophy in senescence-accelerated mouse-prone 1 (SAMP1) mice. For 15 weeks, SAMP1 mice were intragastrically administered vehicle or β-cryptoxanthin. At 35 weeks of age, the skeletal muscle mass in SAMP1 mice was reduced compared with that in control senescence-accelerated mouse-resistant 1 (SAMR1) mice. β-cryptoxanthin increased muscle mass with an increase in the size of muscle fibers in the soleus muscle of SAMP1 mice. The expressions of autophagy-related factors such as beclin-1, p62, LC3-I, and LC3-II were increased in the soleus muscle of SAMP1 mice; however, β-cryptoxanthin administration inhibited this increase. Unlike in SAMR1 mice, p62 was punctately distributed throughout the cytosol in the soleus muscle fibers of SAMP1 mice; however, β-cryptoxanthin inhibited this punctate distribution. The cross-sectional area of p62-positive fiber was smaller than that of p62-negative fiber, and the ratio of p62-positive fibers to p62-negative fibers was increased in SAMP1 mice. β-cryptoxanthin decreased this ratio in SAMP1 mice. Furthermore, β-cryptoxanthin decreased the autophagy-related factor expression in murine C2C12 myotube. The autophagy inhibitor bafilomycin A1, but not the proteasome inhibitor MG132, inhibited the β-cryptoxanthin-induced decrease in p62 and LC3-II expressions. These results indicate that β-cryptoxanthin inhibits the p62 accumulation in fibers and improves muscle atrophy in the soleus muscle of SAMP1 mice.

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Making Mice Mighty: recent advances in translational models of load-induced muscle hypertrophy

Journal of Applied Physiology ◽

10.1152/japplphysiol.00319.2020 ◽

2020 ◽

Vol 129 (3) ◽

pp. 516-521 ◽

Cited By ~ 1

Author(s):

Kevin A. Murach ◽

John J. McCarthy ◽

Charlotte A. Peterson ◽

Cory M. Dungan

Keyword(s):

Skeletal Muscle ◽

Muscle Hypertrophy ◽

Muscle Growth ◽

Therapeutic Interventions ◽

Loss Of Function ◽

Hypertrophic Response ◽

Advantages And Disadvantages ◽

Muscle Loading ◽

Specific Factors

The ability to genetically manipulate mice allows for gain- and loss-of-function in vivo, making them an ideal model for elucidating mechanisms of skeletal muscle mass regulation. Combining genetic models with mechanical muscle loading enables identification of specific factors involved in the hypertrophic response as well as the ability to test the requirement of those factors for adaptation, thereby informing performance and therapeutic interventions. Until recently, approaches for inducing mechanically mediated muscle hypertrophy (i.e., resistance-training analogs) have been limited and considered “nontranslatable” to humans. This mini-review outlines recent translational advances in loading-mediated strategies for inducing muscle hypertrophy in mice, and highlights the advantages and disadvantages of each method. The skeletal muscle field is poised for new breakthroughs in understanding mechanisms regulating load-induced muscle growth given the numerous murine tools that have very recently been described.

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Phosphorylation of eukaryotic initiation factor 4E is dispensable for skeletal muscle hypertrophy

AJP Cell Physiology ◽

10.1152/ajpcell.00380.2019 ◽

2019 ◽

Vol 317 (6) ◽

pp. C1247-C1255 ◽

Cited By ~ 1

Author(s):

Vandre C. Figueiredo ◽

Davis A. Englund ◽

Ivan J. Vechetti ◽

Alexander Alimov ◽

Charlotte A. Peterson ◽

...

Keyword(s):

Skeletal Muscle ◽

Cyclin D1 ◽

Ribosome Biogenesis ◽

Muscle Hypertrophy ◽

Phosphorylation Site ◽

Initiation Factor ◽

Eukaryotic Initiation Factor ◽

Eukaryotic Initiation Factor 4E ◽

Skeletal Muscle Hypertrophy ◽

Mechanical Overload

The eukaryotic initiation factor 4E (eIF4E) is a major mRNA cap-binding protein that has a central role in translation initiation. Ser209 is the single phosphorylation site within eIF4E and modulates its activity in response to MAPK pathway activation. It has been reported that phosphorylation of eIF4E at Ser209 promotes translation of key mRNAs, such as cyclin D1, that regulate ribosome biogenesis. We hypothesized that phosphorylation at Ser209 is required for skeletal muscle growth in response to a hypertrophic stimulus by promoting ribosome biogenesis. To test this hypothesis, wild-type (WT) and eIF4E knocked-in (KI) mice were subjected to synergist ablation to induce muscle hypertrophy of the plantaris muscle as the result of mechanical overload; in the KI mouse, Ser209 of eIF4E was replaced with a nonphosphorylatable alanine. Contrary to our hypothesis, we observed no difference in the magnitude of hypertrophy between WT and KI groups in response to 14 days of mechanical overload induced by synergist ablation. Similarly, the increases in cyclin D1 protein levels, ribosome biogenesis, and translational capacity did not differ between WT and KI groups. Based on these findings, we conclude that phosphorylation of eIF4E at Ser209 is dispensable for skeletal muscle hypertrophy in response to mechanical overload.

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The Regulation of Polyamine Pathway Proteins in Models of Skeletal Muscle Hypertrophy and Atrophy - a potential role for mTORC1

AJP Cell Physiology ◽

10.1152/ajpcell.00078.2021 ◽

2021 ◽

Author(s):

Michael Tabbaa ◽

Tania Ruz Gomez ◽

Dean G. Campelj ◽

Paul Gregorevic ◽

Alan Hayes ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Muscle Mass ◽

Food Deprivation ◽

Muscle Hypertrophy ◽

Metabolic Stress ◽

Dependent Manner ◽

Serine Threonine Kinase ◽

Spermine Synthase ◽

Mechanical Overload

Polyamines have been shown to be absolutely required for protein synthesis and cell growth. The serine/threonine kinase, the mechanistic target of rapamycin complex 1 (mTORC1), also plays a fundamental role in the regulation of protein turnover and cell size, including in skeletal muscle, where mTORC1 is sufficient to increase protein synthesis and muscle fiber size, and is necessary for mechanical overload-induced muscle hypertrophy. Recent evidence suggests that mTORC1 may regulate the polyamine metabolic pathway; however, there is currently no evidence in skeletal muscle. This study examined changes in polyamine pathway proteins during muscle hypertrophy induced by mechanical overload (7 d), with and without the mTORC1 inhibitor, rapamycin, and during muscle atrophy induced by food deprivation (48 h) and denervation (7 d) in mice. Mechanical overload induced an increase in mTORC1 signalling, protein synthesis and muscle mass, and these were associated with rapamycin-sensitive increases in adenosylmethione decarboxylase 1 (Amd1), spermidine synthase (SpdSyn) and c-Myc. Food deprivation decreased mTORC1 signalling, protein synthesis and muscle mass, accompanied by a decrease in spermidine/spermine acetyltransferase 1 (Sat1). Denervation, resulted increased mTORC1 signalling and protein synthesis, and decreased muscle mass, which was associated with an increase in SpdSyn, spermine synthase (SpmSyn) and c-Myc. Combined, these data show that polyamine pathway enzymes are differentially regulated in models of altered mechanical and metabolic stress, and that Amd1 and SpdSyn are, in part, regulated in a mTORC1-dependent manner. Furthermore, these data suggest that polyamines may play a role in the adaptive response to stressors in skeletal muscle.

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Expression of β-catenin is necessary for physiological growth of adult skeletal muscle

AJP Cell Physiology ◽

10.1152/ajpcell.00644.2005 ◽

2006 ◽

Vol 291 (1) ◽

pp. C185-C188 ◽

Cited By ~ 42

Author(s):

Dustin D. Armstrong ◽

Vicki L. Wong ◽

Karyn A. Esser

Keyword(s):

Skeletal Muscle ◽

Cell Fate ◽

Cross Sectional ◽

Adult Skeletal Muscle ◽

Fiber Analysis ◽

Mechanical Overload ◽

Inappropriate Expression ◽

Multiple Signaling ◽

Embryonic Pattern Formation

Expression of β-catenin is known to be important for developmental processes such as embryonic pattern formation and determination of cell fate. Inappropriate expression, however, has been linked to pathological states such as cancer. Here we report that expression of β-catenin is necessary for physiological growth of skeletal muscle in response to mechanical overload. Conditional inactivation of β-catenin was induced in control and overloaded muscle through intramuscular injection of adenovirus expressing Cre recombinase in β-catenin floxed mice. Individual muscle fiber analysis was performed to identify positively transfected/inactivated cells and determine fiber cross-sectional area. The results demonstrate that fiber growth is completely inhibited when the β-catenin expression is lost. This effect was cell autonomous, as fibers that did not exhibit recombination in the floxed mice grew to the same magnitude as infected/noninfected fibers from wild-type mice. These findings suggest that β-catenin may be a primary molecular site through which multiple signaling pathways converge in regulating physiological growth.

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Influence of overload on phenotypic remodeling in regenerated skeletal muscle

AJP Cell Physiology ◽

10.1152/ajpcell.2001.281.5.c1686 ◽

2001 ◽

Vol 281 (5) ◽

pp. C1686-C1694 ◽

Cited By ~ 15

Author(s):

A. X. Bigard ◽

J. Zoll ◽

F. Ribera ◽

P. Mateo ◽

H. Sanchez ◽

...

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Lactate Dehydrogenase ◽

Sarcoplasmic Reticulum ◽

Heavy Chain ◽

Type I ◽

Similar Extent ◽

Surgical Ablation ◽

Control Of Gene Expression ◽

Mechanical Overload

We studied the effects of 10 wk of functional overload on the expression of myosin heavy chain (MHC), sarcoplasmic reticulum Ca2+-ATPase isoforms (SERCA), and the activity of several metabolic enzymes in sham and regenerated plantaris muscles. Overload was accomplished by bilateral surgical ablation of its synergists 4 wk after right plantaris muscles regenerated after myotoxic infiltration. The overload-induced muscle enlargement was slightly less in regenerated than in sham muscles [28% ( P < 0.005) and 43% ( P < 0.001), respectively]. Overload led to an increase in type I MHC expression ( P < 0.01) to a similar extent in sham and regenerated plantaris, while the expected shift from type IIb to type IIa MHC was less marked in regenerated than in sham plantaris. The overload-induced decrease in the expression of the fast SERCA isoform and in the activity of the M subunit of lactate dehydrogenase occurred to a similar extent in sham and regenerated plantaris [66% ( P < 0.01) and 27% ( P < 0.005), respectively]. In conclusion, the lesser responses of muscle mass and fast MHC composition of regenerated plantaris to mechanical overload suggest an alteration of the transcriptional, translational, and/or posttranslational control of gene expression in regenerated muscle.

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